Neurodegenerative diseases with protein depositions comprise a wide range of clinical symptoms. They are characterized by pathologically abnormal, global or local concentrations of proteins or protein fragments (peptides) and deposits or aggregations triggered by them, which due to prior dimerization or oligomerization may result in ordered structures (e.g. fibrils) and which can even form crystalline protein structures (e.g. β-amyloid in Alzheimer plaques).
Diseases hiding behind this pathology include Huntington's chorea, in which Huntingtin accumulates and is deposited in core regions of the brain. Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disease believed to be caused by the protein ataxin-2, which has been detected in an agglomerated form. In the case of Lewy body dementia (LBD), the agglomerated form of the protein α-synuclein can be determined pathophysiologically, which also brings together the clinical characteristics of Parkinson's disease and multiple-system atrophy (MSA) in the group of the “synucleinopathies”. Another group of neurodegenerative diseases is formed by the tauopathies, in which the cytoskeletal protein tau protein clusters to fibrillar structures (PHFs or tangles).
A large group of such protein deposits can be observed with amyloidoses. Large quantities of abnormally modified proteins appear which are deposited as insoluble small fibres (fibrils). In the case of the amyloidoses, it is a perturbation in the folding of a normally soluble protein which is the underlying cause. These proteins congregate through abnormal concentrations to larger β-pleated sheet structures and eventually form fibrils.
As the fibrils are relatively resistant to the body's own defence mechanisms (phagocytosis and proteolysis), they cannot be completely removed from the organs affected. These deposits then destroy the architecture of the organs, the result of which is malfunctions and even total failure. Amyloidoses are a pathological deposition process which can be triggered by various metabolic disorders and which results in different chronic changes or diseases, depending on the organ affected.
A special manifestation of amyloidosis is amyloidosis of aging, which mainly affects the heart and brain. Today, this form is described immunohistochemically as AS-amyloidosis and is understood to mean all amyloid proteins which cause senile amyloidosis. Although the trigger proteins have not yet been characterized in many cases, frequent occurrence is associated with Alzheimer's disease.
Another peripheral degenerative disease with protein deposition is, for example, inclusion body myositis (IBM), where deposited molecules/peptides are found within muscle fibre which are associated with degenerative organ processes in other places as well, such as β-amyloids and prion protein. The latter is seen, inter alia, as the cause of the inflammatory muscle process with IBM.
Alzheimer's disease, also known as Alzheimer's dementia, presenile sclerosis as well as senile dementia-Alzheimer type, internationally abbreviated to AD, is a neurodegenerative disease which occurs in its most frequent form in people above the age of 65 and is believed to have been responsible for some 29 million cases of dementia in 2007. [R. Brookmeyer et al: Forecasting the global burden of Alzheimer's disease. In: Alzheimer's and Dementia. 3/2007, vol. 3, pp. 186-191]. The cognitive skills deteriorate as the disease advances, which may lead to behavioural disorders and character changes. So-called plaques consisting of aggregated β-amyloid peptides (Aβ) may be found in the brains of those suffering from Alzheimer's. It has so far not been possible to find any definite cause for the disease's sporadic variant but genetic mutations on three different genes are thought to be associated with familial AD. Special allele genotypes of the apolipoprotein E (ApoE), and in particular of the ApoE4, are likewise thought to increase the risk of contracting AD. [Corder, E. H. et al. (1993): Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. In: Science 261 (5123):921-923][Bu, G. (2009): Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy. In: Nat. Rev. Neurosci. 10(5):333-344.]. Demographic developments with their rise in the average age of the population will also see an ever greater number of people developing AD in the next few decades. The prevalence of Alzheimer's increases from 2% in 65-year-olds to 20% in 85-year-olds. Forecasts for the year 2050 predict a prevalence heading towards over 100 million patients. This large number of patients will thus constitute a considerable burden for the population at large. Delaying the pathogenesis by approx. 5 years could not only postpone the individual suffering until the natural death but also substantially reduce the anticipated costs for the community as a whole.
So-called senile plaques and fibrillar tangles (NFTs) are found in the brain of Alzheimer patients upon closer observation of the pathogenetic mechanism. The protein deposits of the plaques consist mainly of amyloid-β peptides. The intracellular neurofibrillary tangles consist of the tau protein. This aggregates to fibrils if it phosphorylates more strongly than normal, i.e. is bound with phosphoric acid residues (“hyperphosphorylation”). It is uncertain whether this tau phosphorylation is secondary in nature or triggers the disease. Neurons dying off cause the cerebral mass to decrease as the disease progresses; this is then referred to as cerebral atrophy. In addition to this, the neurotransmitter acetylcholine is no longer produced in sufficient quantities, which leads to a general reduction in the performance of the brain.
The Aβ-peptides are formed from a precursor protein, the amyloid precursor protein (APP), which is an integral membrane protein. It is a type I transmembrane protein: its large amino terminal end is on the outside of the cell while a smaller carboxyl terminus can be found within the cell. APP is cleaved by proteolytic enzymes, the so-called secretases (α-secretase, β-secretase and γ-secretase), which can result in the Aβ-peptide being released from the precursor protein. There are basically two ways in which APP can be cleaved. The non-amyloidogenic way: APP is cleaved by an α-secretase. This cleavage takes place within the APP part containing the Aβ and it prevents Aβ forming. A large extracellular portion, whose function has not been definitively explained, is then released. The amyloidogenic way: APP is first cleaved by the β-secretase and then by the γ-secretase. This cleavage, which takes place within the transmembrane domain, results in Aβ being released. Both processes can occur at the same time in nerve cells. The Aβ-peptides formed by β- and γ-secretases vary in their length. The main type (Aβ-40) is 40, while a small portion (Aβ-42) is 42 amino acids long. The length of the Aβ is of central pathological importance because the longer Aβ-42 exhibits a considerably higher tendency to aggregation than the shorter Aβ-40.
There are genetic causes which lead to Alzheimer's disease. Approximately one to five percent of those affected exhibit a familial accumulation (familial Alzheimer's disease (FAD)), which can be attributed to mutations of the presenilin-1 gene on chromosome 14, of the presenilin-2 gene on chromosome 1 or of the APP gene on chromosome 21. Down's syndrome with its three copies of chromosome 21, upon which is the APP gene, also increases the risk of developing a form of dementia, possibly Alzheimer's disease. Psychodiagnostic detection in people with this genome mutation is made more difficult, however, by a cognitive impairment usually already present early on.
In the case of Alzheimer's disease, there is also a malfunction of the mitochondria. A blockage of the electron transport chain at Complex IV leads to excessive production of radicals which damage the cell. The question is still unsettled as to whether this blockage is a result of excessive Aβ production or whether Aβ is produced in excessive quantities as an antioxidant against this new oxidative stress. Antioxidative extracts can be used to prevent radical-triggered Aβ production if need be.
ABC transporters form a large family of membrane proteins which actively translocate specific substrates across a cell membrane. ABC transporters belong on the one hand to the primarily active transporters and on the other hand to the membranous ATPases. The ABC transporter superfamily comprises one of the largest known protein families with members in nearly every organism, from bacteria to plants and mammals. The ABC transporters have become a focus of attention in the last few years since it was realised that they are of considerable medical, industrial and economic significance. Tens of thousands of people die of cancer each year because chemotherapy has failed due to the strong expression of ABC transporters in tumour tissue. Mutations in a gene which codes for an ABC transporter can lead to various metabolic diseases in people. All eukaryotic ABC transporters are exporters. Some of them are highly substrate-specific while others are multi-specific. ABC transporters also translocate, inter alia, β-amyloid and are therefore regarded as part of the pathogenetic mechanism which leads to AD [Pahnke et al. 2008: Clinico-pathological function of cerebral ABC transporters—implications for the pathogenesis of Alzheimer's disease. Current Alzheimer Research 5, 396-406; Pahnke et al. 2009: Alzheimer's disease and blood-brain barrier function—Why have anti-β-amyloid therapies failed to prevent dementia progression? NeurosciBiobehavR 33:1099-1108].